IE64304B1 - Process for the lactonization of mevinic acids and analogs thereof - Google Patents
Process for the lactonization of mevinic acids and analogs thereofInfo
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- IE64304B1 IE64304B1 IE232489A IE232489A IE64304B1 IE 64304 B1 IE64304 B1 IE 64304B1 IE 232489 A IE232489 A IE 232489A IE 232489 A IE232489 A IE 232489A IE 64304 B1 IE64304 B1 IE 64304B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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Abstract
A process for the lactonization of mevinic acid HMG-CoA reductase inhibitors and analogs thereof is disclosed.
Description
BACKGROUND OF THE INVENTION Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
Mevacor® (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: wherein: Z* is hydrogen, C^-s alkyl or C1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and R* is: wherein Q is R2— C— or R3 —CH; R2 is h or OH; and Jh3 ' R2 is hydrogen or methyl; and a, b, c, and d represent optional double bonds, especially where b and d represent double bonds or a, b, c, and d are all single bonds, provided j that when a is a double bond, Q is C= or C CH3 A The preparation of the naturally occurring compounds and their semi-synthetic analogs leads to a mixture of the lactone and dihydroxy acid forms. Mevacor® is marketed in the lactone form and thus it is of considerable importance to employ a high yield efficient method for the lactonization of the free acid or salt form. In the past, lactonization of the free acid or ammonium salt was effected by heating these substrates in a neutral organic solvent such as toluene, ethyl acetate, or isopropyl acetate at or near reflux. The lactonization is catalyzed by the presence of acid. The necessary acidity arises either through the ambient acidity of the substrate itself or by the addition of a stonger acid to effect lactonization at a lower temperature.
I The use of conventional acid catalyzed lactonization in a neutral organic solvent to prepare HMG-CoA reductase inhibitors is described in published European patent application no. 0183132.
Lactonization is an equilibrium process, and in order to obtain a high yield of the lactone product, some means must be employed to shift the equilibrium to the lactone side of the equation: Dihydroxy acid (or NH44· salt) Lactone + H2O (+NH3) In the prior procedures, lactonization is forced to near completion by removing the reaction by-products (water, ammonia) from the reaction mixture by means of azeotropic distillation and/or nitrogen sweep.
The removal of water, and in the case of the ammonium salt ammonia, shifts the position of equilibrium to the lactone side.
Prior lactonization procedures exhibited several disadvantages. Typically the hydroxy acid substrate acted as the acid catalyst and thus as the substrate was consumed, the rate of reaction decreased requiring longer reaction times and allowing for increased by-product formation. Under the reaction conditions, the product 3-hydroxylactone is exposed for prolonged periods of time to the free acid which leads to increased amounts of a dimer (1) which results from an esterification reaction between the 3-hydroxyl group of the 3-hydroxylactone and the free acid.
The above dimer impurity has proved to be difficult to separate from the desired lactone product even with careful recrystallization techniques. The presence of the dimer, of course, lowers the overall yield and purity of the lactone product. Efforts to minimize the formation of the dimer have led to the use of high dilution in the lactonization reaction, however, this technique compromises the efficiency of the reaction.
A second impurity, resulting from dehydration of the 3-hydroxyl group on the lactone ring, was also * observed using prior lactonization conditions. This impurity was likewise only inefficiently removed by • recrystallization, resulting in diminished yields. The present invention alleviates this problem.
DETAILED DESCRIPTION OF THE INVENTION The instant invention relates to a novel process for the conversion of mevinic acid HMG-CoA reductase inhibitors or analogs thereof into a lactone. The present process enables the shifting of the lactonization equilibrium by the continuous and selective removal of the lactone product from the reaction mixture. To employ this novel approach in the present lactonization equilibrium, it was necessary to identify a reaction medium in which the lactone product would be less soluble than the unlactonized starting material; and find a selective crystallization method for the removal of the lactone without entrainment of process impurities or starting material.
Specifically the instant invention involves treating the free hydroxy acid or ammonium or metal salt derivative of a mevinic acid or analog thereof in an acetic acid medium, or other water miscible organic solvent which exhibits a sufficient solubility difference between the hydroxy acid and lactone, and a strong acid catalyst. After the free hydroxy acid-lactone equilibrium is established, water is gradually added in an amount sufficient to effect complete crystallization of the lactone from the reaction medium. This removal of the lactone continuously shifts the equilibrium to the lactone side and thus drives the lactonization to completion. In the instant procedure, the lactone is continuously removed from the reaction medium as it is formed, minimizing the lactone’s exposure to the reaction conditions and thus minimizing the potential for its further reaction to form dimers. Thus one obtains a lactone product free from the impurities complicating the prior art lactonization procedures.
The instant invention can be depicted as: wherein R is Ci_iq alkyl; 0 Ri is CH3, CH2OH, CH2OCR2, CO2R3 HNR4R5, OH, CH2OR2 or CH2NR4R5; R2 is Cj-5 alkyl; R3 is H or Ci_5 alkyl; R4 and R5 are independently selected frc.t H or Ci_io alkyl; a and b are both double bonds or one of a and b is a single bond or both a and b are single bonds.
Major advantages realized in the instant invention compared to the prior art are increased process productivity and product purity. The prior art procedures are conducted in a highly dilute medium (Ό.1Μ) in order to minimize dimer formation. The instant invention allows for lactonization at much higher concentrations (~.24M) thus markedly improving productivity. Furthermore, the prior art procedure requires an additional step wherein the solvent is concentrated prior to isolation of the lactone; in the present procedure the lactone is isolated directly from the reaction mixture. Again the instant procedure demonstrates a greater efficiency than the prior art.
With respect to product purity, the prior art method yielded a semi-pure product which contained from 0.4 to 0.8% of a difficult-to-remove dimeric impurity, whereas the levels of this impurity under the-present lactonization conditions is reduced to less than 0.2%.
The specific hydroxy acids or salts derived therefrom, which are employed in the instant invention, are of stucture (I): wherein: R is Ci_io alkyl; O Ri is CH3, CH2OH, CH2oBr2, CO2R3, CNR4R5, OH, CH2OR2, or CH2NR4R5; 1' O Z is H or NH4+ or a metal cation; R2 is Ci_5 alkyl; R3 is H or Ci_5 alkyl; R4 and R5 are independently selected from H or Cy_5 alkyl; a and b are both double bonds or one of a and b is a single bond or both a and b are single bonds.
The solvents employed are water miscible organic solvents. The particular solvent is determined by the characteristics of crystallization, i.e. the solubility difference between the hydroxy acid or salt and the lactone, the crystallization selectivity and the kinetics of crystallization, in the water-organic solvent mixture. Suitable solvents include acetic acid, acetonitrile, acetone and methanol preferably acetic acid, acetonitrile or acetone.
The rate of lactonization depends on the strength and concentration of the acid catalyst. Any inorganic or organic acid of acidity sufficient to catalyze the formation of a lactone may be employed. Illustrative of suitable acids which may be employed are formic, phosphoric, trifluoroacetic, sulfuric, hydrochloric, perchloric, p-toluenesulfonic and methanesulfonic acid.
The lactonization may be conducted over a temperature range of 20 ’C to 30"C, preferably 20-25’C. It is critical that the temperature not be allowed to rise above 30°C as this leads to increased by-product formation.
Preferred metal cations are cations of alkali metals, such as sodium or potassium, cations of alkaline earth metals, such as calcium or magnesium, or cations of other metals such as aluminum, iron, zinc, copper, nickel or cobalt. The alkali metal cations, alkaline earth metal cations, and aluminum cations are preferred; the sodium, calcium and aluminum cations being most preferred.
In one embodiment of the instant process is the compounds of formula (I) wherein: R is C]_io alkyl, Rl is CH3; and Z is H or NH4+.
In one class of this embodiment, R is sec-butyl or 1,l-dimethylpropyl and Ri is CH3, Z is NH4+, a and b are double bonds, the organic solvent is acetic acid, acetonitrile or acetone and the acid catalyst is trifluoracetic acid or methanesulfonic acid. In one subclass R is 1,l-dimethylpropyl, the organic solvent is acetic acid and the acid catalyst is trifluoracetic or methanesulfonic acid preferably methanesulfonic acid. In a second subclass, R is sec-butyl, the organic solvent is acetone, acetic acid or acetonitrile, and the acid catalyst is trifluoracetic acid or methanesulfonic acid.
The following examples illustrate the process of the instant invention and are not to be considered as limiting the invention set forth in the claims appended hereto.
EXAMPLE 1 Preparation of 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one..
Ammonium 7-[1,2,6,7,8,8a(R)-hexahydro-2(S), 6(R)-dimethyl-8 (S)-(2,2-dimethylbutyryloxy)-1(S) naphthyl]-3(R),5(R)-dihydroxyheptanoate (12.5 grams, 97.9 wt. % purity by HPLC, 27.0 mmol) was stirred with a mixture of acetic acid (40 ml), water (20 ml) and trifluoroacetic acid (3.84 g, 33.7 mmol, 2.5 ml) under a nitrogen atmosphere for 3 hours at 23-26eC.
After the 3 hour age period, the first portion of water (10 ml) was added at once. From that point on, the addition of the second portion of water (15 ml) was carried out uniformly over a period of 3 hours. The product lactone began crystallizing out during this time period.
The last portion of water (35 ml) was added over a period of 1 hour. The sample was then agitated for an additional 2 hours. The trifluoroacetic acid was neutralized with concentrated ammonium hydroxide (5.0 ml, 1.35 g NH3, 79 mmol) which was added slowly with cooling of the batch mixture. The batch was then agitated for 1 hour and then the product filtered and washed with about 100 ml of an acetic acid-water mixture (1:2 v/v) followed by washing with 100 ml of water. The filter cake was dried to constant weight in vacuo at 35°C under a slow nitrogen sweep to yield the titled compound in 98.0% purity (HPLC). The level of dimer was <0.2%.
EXAMPLE 2 Preparation of 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1 (S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Ammonium 7-(1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8 (S)-(2,2-dimethylbutyryloxy)-1(S)naphthyl]-3(R),5(R)-dihydroxyheptanoate (12.5 g, 95.4 wt. % purity by HPLC, 27.6 mmol), and BHA (butylated hydroxy anisole) (0.075g) were suspended in a mixture of acetic acid (40 ml) and water (20 ml) at 22-25°C under nitrogen. MSA (methanesulfonic acid) (2.94 g, 2.00 ml, 30.6 mmol) was added to the above suspension.
After 2 hours, water (10 ml) was added in one portion. From that point on, the addition of the second portion of water (15 ml) was carried out uniformly over a period of 3 hours. The last portion of water (35 ml) was added over a period of 1 hour, and the sample agitated for an additional hour. The methanesulfonic acid was neutralized with concentrated ammonium hydroxide (4.0 ml, 1.35 g NH3, 63.2 mmol) which was added slowly with cooling of the batch mixture. The batch was then agitated for 1 hour, and then the product filtered and washed with about 100 ml of an acetic acid-water mixture (1:2 v/v) followed by washing with 100 ml of water. The filter cake was dried to constant weight in vacuo at 35°C under a slow nitrogen sweep to yield the titled compound in 96.5% purity (HPLC). The level of dimer was <0.2%.
EXAMPLE 3 Preparation of 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2 (S),6(R)-dimethy1-1,2,6,7,8,8a(R)-hexahydronaphthyl-1 (S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran2-one.
The titled compound is prepared following the procedure of Example 1 or Example 2 but substituting Ammonium 7-(1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)d imethy1-8(S)-(2-methylbutyryloxy)-1(S)-naphty]3(R),5(R)-dihydroxyheptanoate as the substance to be lactonized. Alternatively acetone or acetonitrile may be substituted as the organic solvent, but with a neutral solvent, the acid is neutralized in the presence of a pH probe to pH 6.
Claims (26)
1. compound of A process for the structure (I): lactonization of a o wherein: R is Ci_io alkyl; 0 R x is CH 3 , CH 2 OH, CH 2 OCR 2 , CO 2 R 3 , CNR4R5, OH, CH 2 OR 2 , or CH 2 NR4R5; O Z is H or NH4+ or a metal cation; R 2 is Cx_5 alkyl; R 3 is H or Cx_5 alkyl; R4 and R5 are independently selected from H or Ci_5 alkyl; a and b are both double bonds or one of a and b is ε single bond or both a and b are single bonds; which comprises: (A) treating (I) with a mixture of a water miscible organic solvent, water and an acic catalyst under an inert gas atmosphere for about 2-3 hours at 20-25°C; (3) treatment of the reaction mixture with additional water to precipitate the product lactone (II) as a crystalline mass.
2. A process according to Claim 1 wherein: R is Ci_io alkyl, Rj is CH3; and Z is H or NH4+.
3. A process according to Claim 2 wherein R is sec-butyl or 1,1-dimethylpropyl, and a and b are double bonds .
4. A process according to Claim 3 wherein: the organic solvent is selected from acetic acid, acetonitrile or acetone.
5. A process according to Claim 4 wherein the acid catalyst is selected from: formic, phosphoric, trifluoroacetic, sulfuric, hydrochloric, perchloric, p-toluenesulfonic and methanesulfonic acid.
6. A process according to Claim 5 wherein R is 1,1-dimethylpropyl.
7. A process according to Claim 6 wherein the organic solvent is acetic acid and Z is NH4+.
8. A process according to Claim 7 wherein the acid catalyst is trifluoroacetic acid, or 5 methanesulfonic acid.
9. A process according to Claim 8 wherein the acid catalyst is methanesulfonic acid.
10. A process according to Claim 5 wherein R is sec-butyl. 1q
11. A process for the preparation of a compound of the structure (II): wherein: R is C 3 _ 10 alkyl; ll Ri is ch 3 , ch 2 oh, ch 2 ocr 2 , CO 2 R 3 , CNR4R5, OH, CH 2 OR 2 , or CH 2 NR 4 R 5 ; Z is H or NH 4 + or a metal cation; R 2 is C 3 _5 alkyl; R 3 is H or C 3 _5 alkyl; - 15 R4 and R5 are independently selected from H or Ci_5 alkyl; a and b are both double bonds or one of a and b are single bonds; 5 which comprises treating a compound of the structure (I) wherein R, R lr a and b are defined in relation to structure (II) and wherein Z is Η, NH4+ or a metal cation in a water miscible organic solvent with a strong 10 acid catalyst and thereafter gradually adding water until crystallisation of the lactone from the reaction medium is effected, whereby the compound of structure (II) is produced containing less than 0.2% of dimeric impurity.
12. A process according to claim 11 wherein R is 15 c l-l0 alkyl, R^ is CH3 and Z is H + or NH 4 +.
13. A process according to claim 11 wherein the solvent is acetic acid, acetonitrile or acetone.
14. A process according to any of claims 11 to 13 wherein Z is NH4+. - 16
15. A process according to any of claims 11 to 14 wherein the strong acid catalyst is formic, phosphoric, trifluoracetic, sulfuric, hydrochloric, perchloric ptoluenesulfonic or methanesulfonic.
16. A compound of the structure (II) (II) wherein: R is Ci-iQ alkyl Λ R! is CH 3 , CH 2 OH; CH 2 OCR 2> C02 r 3 CNR4R5, OH, CH 2 OR 2 , or CH 2 NR4R 5 ; II Z is H or NH4+ or a metal cation; R 2 is C 3 _5 alkyl; R 3 is H or C 3 _5 alkyl; R4 and R5 are independently selected from H or C 3 _5 alkyl; a and b are both double bonds or one of a and b is a single bond or both a and b are single bonds; containing less than 0.2% of dimeric impurity.
17. A compound according to claim 16 wherein R^ is 5 CH 3 .
18. A compound according to claim 16 wherein Ri is OH.
19. A compound according to any of claim 16 to 18 10 wherein R is sec-butyl or 1,1-dimethylpropyl and a and b are double bonds.
20. 6(R)-[2-[8(S)-(2,2-dimethylbutynyloxy)-2(S), 6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronapthyl15 1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2one containing less than 0.2% of dimeric impurity.
21. 6(R)-[2-[8(S) - (S-methylbutyryloxy)-2(S),6 (R) dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl) 20 4 (R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one containing less than 0.2% of dimeric impurity. i.
22. A process according to Claim 1, substantially as hereinbefore described and exemplified.
23. A lactone (II) whenever obtained by a process claimed in a preceding claim . 5
24. A process for preparing a compound as claimed in Claim 16, substantially as hereinbefore described and exemplified.
25. A compound as claimed in Claim 16, whenever prepared by a process claimed in any one of Claims 11-15 or 10 24.
26. A compound as claimed in Claim 16, substantially as hereinbefore described and exemplified.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/221,475 US4916239A (en) | 1988-07-19 | 1988-07-19 | Process for the lactonization of mevinic acids and analogs thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IE892324L IE892324L (en) | 1990-01-19 |
| IE892324A1 IE892324A1 (en) | 1991-06-19 |
| IE64304B1 true IE64304B1 (en) | 1995-07-26 |
Family
ID=22827965
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE232489A IE64304B1 (en) | 1988-07-19 | 1989-07-18 | Process for the lactonization of mevinic acids and analogs thereof |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US4916239A (en) |
| EP (1) | EP0351918B1 (en) |
| JP (3) | JPH0273078A (en) |
| KR (1) | KR970011286B1 (en) |
| CN (1) | CN1022831C (en) |
| AT (1) | ATE111459T1 (en) |
| AU (1) | AU609319B2 (en) |
| CA (1) | CA1287639C (en) |
| CS (1) | CS274640B2 (en) |
| CY (1) | CY1813A (en) |
| DE (1) | DE68918191C5 (en) |
| DK (1) | DK173115B1 (en) |
| ES (1) | ES2058475T3 (en) |
| FI (1) | FI92695C (en) |
| HK (1) | HK136894A (en) |
| HR (1) | HRP930685B2 (en) |
| HU (2) | HU202511B (en) |
| IE (1) | IE64304B1 (en) |
| IL (1) | IL90925A (en) |
| LV (1) | LV11033B (en) |
| NO (1) | NO172800C (en) |
| NZ (1) | NZ229879A (en) |
| PT (1) | PT91191B (en) |
| SI (1) | SI8911362A (en) |
| YU (1) | YU47492B (en) |
| ZA (1) | ZA895458B (en) |
Families Citing this family (89)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4916239A (en) * | 1988-07-19 | 1990-04-10 | Merck & Co., Inc. | Process for the lactonization of mevinic acids and analogs thereof |
| GB9007738D0 (en) * | 1990-04-05 | 1990-06-06 | British Bio Technology | Compounds |
| US5223415A (en) * | 1990-10-15 | 1993-06-29 | Merck & Co., Inc. | Biosynthetic production of 7-[1',2',6',7',8',8a'(R)-hexahydro-2'(S),6'(R)-dimethyl-8'(S)-hydroxy-1'(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid (triol acid) |
| US5250435A (en) * | 1991-06-04 | 1993-10-05 | Merck & Co., Inc. | Mutant strains of Aspergillus terreus for producing 7-[1,2,6,7,8,8a(R)-hexa-hydro-2(S),6(R)-dimethyl-8(S)-hydroxy-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid (triol acid),I) |
| AU660132B2 (en) * | 1992-12-21 | 1995-06-08 | Bayer Aktiengesellschaft | Substituted 4-phenyl-pyridones and 4-phenyl-2-alkoxypyridine |
| DK0680320T3 (en) * | 1993-01-19 | 1999-10-25 | Warner Lambert Co | Stable oral CI-981 preparation and method of preparation thereof |
| IN186879B (en) * | 1997-10-28 | 2001-12-01 | Ranbaxy Lab Ltd | |
| IN186880B (en) * | 1997-10-28 | 2001-12-01 | Ranbaxy Lab Ltd | |
| ZA9810764B (en) * | 1998-04-22 | 1999-08-13 | Ranbaxy Lab Ltd | An improved process of lactonization in the preparation of statins. |
| CA2240983A1 (en) | 1998-06-18 | 1999-12-18 | Yong Tao | Process to manufacture simvastatin and intermediates |
| AU1683000A (en) * | 1998-12-10 | 2000-06-26 | Kaneka Corporation | Process for producing simvastatin |
| SK282679B6 (en) * | 1999-04-16 | 2002-11-06 | Biotika, A. S. | Process of isolation of lovastatin from fermentation broth |
| HUP0103611A2 (en) * | 1999-06-29 | 2009-10-28 | Kaneka Corp | Process for selective lactonization |
| WO2001030773A2 (en) | 1999-10-27 | 2001-05-03 | Merck & Co., Inc. | Lactonization process |
| HUP0301214A2 (en) | 2000-03-03 | 2003-08-28 | Plus Chemicals S.A. | A process for purifying lovastatin and simvastatin with reduced levels of dimeric impurities |
| NL1017548C2 (en) * | 2001-03-09 | 2002-09-10 | Synthon Bv | A lactonization process. |
| US6797831B2 (en) * | 2001-05-18 | 2004-09-28 | Aurobindo Pharma Limited | Process for lactonization to produce simvastatin |
| KR100407758B1 (en) * | 2001-08-27 | 2003-12-01 | 씨제이 주식회사 | Process of lactonization in the preparation of statins |
| KR100502834B1 (en) * | 2002-03-25 | 2005-07-20 | 보령제약 주식회사 | The preparation method of simvastatin by improved process of lactonization and its purification process |
| US20050113577A1 (en) * | 2002-04-16 | 2005-05-26 | Karki Shyam B. | Solid forms of slats with tyrosine kinase activity |
| AR040588A1 (en) | 2002-07-26 | 2005-04-13 | Schering Corp | PHARMACEUTICAL FORMULATION INCLUDING AN INHIBITOR OF CHOLESTEROL ABSORPTION AND AN INHIBITOR OF A HMGCO TO REDUCTASE |
| US20040132771A1 (en) * | 2002-12-20 | 2004-07-08 | Pfizer Inc | Compositions of choleseteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors |
| ATE407670T1 (en) | 2002-12-20 | 2008-09-15 | Pfizer Prod Inc | DOSAGE FORM CONTAINING A CETP INHIBITOR AND A HMG-COA REDUCTASE INHIBITOR |
| KR20050098313A (en) | 2003-02-11 | 2005-10-11 | 플러스 케미칼스 비.브이. | Process for preparing simvastatin having controlled ranges of simvastatin dimer content |
| AU2004266740B2 (en) | 2003-08-21 | 2010-08-26 | Merck Frosst Canada Ltd | Cathepsin cysteine protease inhibitors |
| KR20060109926A (en) | 2003-11-19 | 2006-10-23 | 메타베이시스 테라퓨틱스, 인크. | Novel phosphorus-containing thyromimetics |
| BRPI0418644A (en) * | 2004-03-30 | 2007-05-29 | Lupin Ltd | process for the preparation of a compound |
| DE602004023004D1 (en) * | 2004-09-08 | 2009-10-15 | Jubilant Organosys Ltd | IMPROVED METHOD OF LACTONIZATION IN THE PRODUCTION OF STATINES |
| CA2581596A1 (en) * | 2004-09-29 | 2006-04-13 | Schering Corporation | Combinations of substituted azetidonones and cb1 antagonists |
| WO2006059346A2 (en) * | 2004-12-01 | 2006-06-08 | Morepen Laboratories Limited | An improved process for lactonization to produce highly pure statins |
| RU2394820C2 (en) | 2004-12-09 | 2010-07-20 | Мерк Шарп Энд Домэ Корп. | Oestrogen receptor modulators |
| DK1855674T3 (en) | 2005-03-02 | 2014-10-20 | Merck Sharp & Dohme | COMPOSITION TO INHIBIT CATHEPSIN K |
| US8362075B2 (en) | 2005-05-17 | 2013-01-29 | Merck Sharp & Dohme Corp. | Cyclohexyl sulphones for treatment of cancer |
| EP1741427A1 (en) | 2005-07-06 | 2007-01-10 | KRKA, D.D., Novo Mesto | Pharmaceutical composition comprising simvastatin and ezetimibe |
| WO2007020079A2 (en) * | 2005-08-17 | 2007-02-22 | Synthon B.V. | Orally disintegratable simvastatin tablets |
| TW200804345A (en) * | 2005-08-30 | 2008-01-16 | Novartis Ag | Substituted benzimidazoles and methods of preparation |
| US20070117996A1 (en) * | 2005-11-21 | 2007-05-24 | Srinivasulu Gudipati | Process for preparing simvastatin |
| BRPI0620255A2 (en) * | 2005-12-21 | 2011-11-08 | Schering Corp | use of cholesterol lowering agents and / or h3 receptor antagonist / inverse agonist |
| WO2007075555A2 (en) * | 2005-12-21 | 2007-07-05 | Schering Corporation | Combination of an h3 antagonist/inverse agonist and an appetite suppressant |
| GB0603041D0 (en) | 2006-02-15 | 2006-03-29 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| PL2010528T3 (en) | 2006-04-19 | 2018-03-30 | Novartis Ag | 6-o-substituted benzoxazole and benzothiazole compounds and methods of inhibiting csf-1r signaling |
| EP2059241A1 (en) * | 2006-09-05 | 2009-05-20 | Schering Corporation | Pharmaceutical combinations for lipid management and in the treatment of atherosclerosis and hepatic steatosis |
| EP2083831B1 (en) | 2006-09-22 | 2013-12-25 | Merck Sharp & Dohme Corp. | Method of treatment using fatty acid synthesis inhibitors |
| US20110218176A1 (en) | 2006-11-01 | 2011-09-08 | Barbara Brooke Jennings-Spring | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
| SI2805945T1 (en) | 2007-01-10 | 2019-09-30 | Msd Italia S.R.L. | Amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors |
| EP2132177B1 (en) | 2007-03-01 | 2013-07-17 | Novartis AG | Pim kinase inhibitors and methods of their use |
| KR20100017866A (en) | 2007-05-21 | 2010-02-16 | 노파르티스 아게 | Csf-1r inhibitors, compositions, and methods of use |
| CA2690191C (en) | 2007-06-27 | 2015-07-28 | Merck Sharp & Dohme Corp. | 4-carboxybenzylamino derivatives as histone deacetylase inhibitors |
| US20090048335A1 (en) * | 2007-08-17 | 2009-02-19 | Venkata Naga Mandava | Process for preparing simvastatin |
| WO2009082437A2 (en) | 2007-12-21 | 2009-07-02 | Ligand Pharmaceuticals Incorporated | Selective androgen receptor modulators (sarms) and uses thereof |
| CA2716671A1 (en) * | 2008-02-27 | 2009-09-03 | Thommen Medical Ag | Implant and method for the manufacture thereof |
| EP2204170A1 (en) | 2008-12-01 | 2010-07-07 | LEK Pharmaceuticals D.D. | Pharmaceutical composition comprising ezetimibe and simvastatin |
| EP2216016A1 (en) | 2009-02-06 | 2010-08-11 | LEK Pharmaceuticals d.d. | Process for the preparation of a pharmaceutical composition comprising ezetimibe |
| US20120046364A1 (en) | 2009-02-10 | 2012-02-23 | Metabasis Therapeutics, Inc. | Novel Sulfonic Acid-Containing Thyromimetics, and Methods for Their Use |
| EP2413932A4 (en) | 2009-04-01 | 2012-09-19 | Merck Sharp & Dohme | Inhibitors of akt activity |
| CA2777043C (en) | 2009-10-14 | 2015-12-15 | Schering Corporation | Substituted piperidines that increase p53 activity and the uses thereof |
| CN104098537A (en) * | 2009-11-20 | 2014-10-15 | 北大医药股份有限公司 | Lactonization method for preparation of statin compound |
| CN101704808A (en) | 2009-11-20 | 2010-05-12 | 西南合成制药股份有限公司 | Lactonization method for preparing statin compound |
| EP2368543A1 (en) | 2010-03-25 | 2011-09-28 | KRKA, tovarna zdravil, d.d., Novo mesto | Method of preparing a granulated pharmaceutical composition comprising simvastatin and/or ezetimibe |
| US8999957B2 (en) | 2010-06-24 | 2015-04-07 | Merck Sharp & Dohme Corp. | Heterocyclic compounds as ERK inhibitors |
| US8518907B2 (en) | 2010-08-02 | 2013-08-27 | Merck Sharp & Dohme Corp. | RNA interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (CTNNB1) gene expression using short interfering nucleic acid (siNA) |
| EP2606134B1 (en) | 2010-08-17 | 2019-04-10 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF HEPATITIS B VIRUS (HBV) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| US8883801B2 (en) | 2010-08-23 | 2014-11-11 | Merck Sharp & Dohme Corp. | Substituted pyrazolo[1,5-a]pyrimidines as mTOR inhibitors |
| WO2012030685A2 (en) | 2010-09-01 | 2012-03-08 | Schering Corporation | Indazole derivatives useful as erk inhibitors |
| WO2012036997A1 (en) | 2010-09-16 | 2012-03-22 | Schering Corporation | Fused pyrazole derivatives as novel erk inhibitors |
| EP3766975A1 (en) | 2010-10-29 | 2021-01-20 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of gene expression using short interfering nucleic acid (sina) |
| US9351965B2 (en) | 2010-12-21 | 2016-05-31 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as ERK inhibitors |
| US8791162B2 (en) | 2011-02-14 | 2014-07-29 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| WO2012143879A1 (en) | 2011-04-21 | 2012-10-26 | Piramal Healthcare Limited | A crystalline form of a salt of a morpholino sulfonyl indole derivative and a process for its preparation |
| US9393224B2 (en) | 2011-08-26 | 2016-07-19 | Osaka University | Prophylactic and/or therapeutic agent for cardiovascular complications of diabetes |
| EP2770987B1 (en) | 2011-10-27 | 2018-04-04 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
| EP2597092A1 (en) | 2011-11-24 | 2013-05-29 | Sterling Biotech Limited | A process for purification of lovastatin |
| WO2013165816A2 (en) | 2012-05-02 | 2013-11-07 | Merck Sharp & Dohme Corp. | SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS |
| AU2013323508B2 (en) | 2012-09-28 | 2017-11-02 | Merck Sharp & Dohme Corp. | Novel compounds that are ERK inhibitors |
| ES2651347T3 (en) | 2012-11-28 | 2018-01-25 | Merck Sharp & Dohme Corp. | Compositions and methods for cancer treatment |
| CA2895504A1 (en) | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | Substituted imidazopyridines as hdm2 inhibitors |
| US9540377B2 (en) | 2013-01-30 | 2017-01-10 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as HDM2 inhibitors |
| US20160194368A1 (en) | 2013-09-03 | 2016-07-07 | Moderna Therapeutics, Inc. | Circular polynucleotides |
| WO2015051479A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| CA2923272A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| EP3094323A4 (en) | 2014-01-17 | 2017-10-11 | Ligand Pharmaceuticals Incorporated | Methods and compositions for modulating hormone levels |
| WO2015120580A1 (en) | 2014-02-11 | 2015-08-20 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
| JO3589B1 (en) | 2014-08-06 | 2020-07-05 | Novartis Ag | Protein kinase c inhibitors and methods of their use |
| EP3525785A4 (en) | 2016-10-12 | 2020-03-25 | Merck Sharp & Dohme Corp. | Kdm5 inhibitors |
| WO2019094311A1 (en) | 2017-11-08 | 2019-05-16 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
| WO2020033282A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
| EP3833667B1 (en) | 2018-08-07 | 2024-03-13 | Merck Sharp & Dohme LLC | Prmt5 inhibitors |
| WO2021126731A1 (en) | 2019-12-17 | 2021-06-24 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
| WO2024180169A1 (en) | 2023-03-02 | 2024-09-06 | Carcimun Biotech Gmbh | Means and methods for diagnosing cancer and/or an acute inflammatory disease |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA81703B (en) * | 1980-02-04 | 1982-09-29 | Merck & Co Inc | New antihypercholesterolemic compounds,intermediates and processes |
| JPS5948418A (en) * | 1982-09-10 | 1984-03-19 | Sankyo Co Ltd | Agent for treatment of excessive lipid peroxide in serum |
| US4582915A (en) * | 1983-10-11 | 1986-04-15 | Merck & Co., Inc. | Process for C-methylation of 2-methylbutyrates |
| US4611068A (en) * | 1984-11-19 | 1986-09-09 | Merck Frosst Canada, Inc. | Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein |
| US4611067A (en) * | 1985-01-31 | 1986-09-09 | Merck & Co., Inc. | Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein |
| US4772626A (en) * | 1986-01-31 | 1988-09-20 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
| PT85109A (en) * | 1986-06-23 | 1987-07-01 | Merck & Co Inc | Process for the preparation of hydroxy-tetrahydropyranone derivatives or corresponding ring opened dihydroxy acids which are hmg-coa reductase inhibitors |
| US4857546A (en) * | 1988-01-07 | 1989-08-15 | Merck & Co., Inc. | Novel HMG-CoA reductase inhibitors |
| US4916239A (en) * | 1988-07-19 | 1990-04-10 | Merck & Co., Inc. | Process for the lactonization of mevinic acids and analogs thereof |
-
1988
- 1988-07-19 US US07/221,475 patent/US4916239A/en not_active Expired - Lifetime
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